Fibrosis is a highly conserved and coordinated wound healing response to injury. In the liver, injury is promoted by immune effector mechanisms that are common across various disease etiologies and even between organs such as lungs, kidneys, heart, and other organs. Thus, the liver represents a useful model to study inflammation and repair, particularly as it is frequently biopsied in clinical contexts. Currently, strong evidence implicates IFNL3/4 polymorphisms and interferon (IFN)-λ3 levels as determinants of the extent of hepatic inflammation and fibrosis in viral and nonviral liver diseases, as well as in governing the severity of nonhepatotropic viral diseases. Interestingly, IFNL3/4 polymorphisms and IFN-λ3 levels correlate with fibrosis extent in other organs such as the lung and kidney. In this review, we discuss the association between IFN-λ and tissue inflammation and fibrosis in human disease and the potential clinical utility of the findings.